Role of Tumor Stem Cells Recurrent Prostate Cancer

癌症的进展从起始的癌症干细胞(CSC)到临床意义，并最终 治疗失败后的复发，是一种不断演变的相互作用的顶峰 在CSC和“干细胞利基”之间。这一提议的假设是，雄激素剥夺 干扰前列腺内皮细胞在调节前列腺雄激素环境中的关键作用 组织微环境，并在调节干细胞的“生态位”，促进/加速出现 去势-复发性前列腺癌为了验证这一假说，提出了以下具体目标。 目的1将表征内皮细胞小窝在循环雄激素跨细胞转运中的作用。 循环中雄激素内吞导致基因AR反式激活的内皮细胞屏障 与内皮细胞动态平衡和信号转导有关，并通过 循环中雄激素的细胞表面受体。目标2将确定剥夺雄激素是否会导致死亡 前列腺癌的血管内皮细胞的一过性或不可逆的扰动 导致组织雄激素环境失调的前列腺微血管(特征为 LC/MS/MS)以及创建/揭开独特的、有针对性的“表位”或“血管地址” (用噬菌体多肽展示技术进行表征)。目标3将确定雄激素的作用 在前列腺CSCs中差异表达的基因和基因通路的剥夺 成体干细胞(ASCs)，鉴定前列腺ASCs/CSCs的细胞表面“表位”指纹，并确定 如果干细胞“生态位”的扰动导致表观遗传调控的HNF-4N失调 前列腺癌干细胞中的转录网络。AIMS 1-3中生成的数据和试剂将支持 目标4的研究重点是开发利用雄激素剥夺使 前列腺特异性治疗：雄激素剥夺使ASC/CSC暴露于靶向 治疗；循环雄激素的跨细胞作用可以在不干扰内皮细胞的情况下被抑制 内皮细胞启动的ASCs/CSCs信号可以被重新编程以诱导干细胞 细胞退出“利基”，致力于分化。

The progression of a cancer from the initiating cancer stem cell (CSC) to clinical significance, and ultimately to recurrence after treatment failure, is the culmination of a continuously evolving reciprocal interaction between the CSC and the "stem cell niche". The hypothesis of this proposal is that androgen deprivation perturbs the critical role of the prostate endothelial cell in regulation of the androgenic milieu of the prostate tissue microenvironment, and in regulation of the stem cell "niche", facilitating/accelerating the emergence of castration-recurrent prostate cancer To validate the hypothesis, the following Specific Aims are proposed. Aim 1 will characterize the role of endothelial cell caveolae in transcytosis of circulating androgens across the endothelial cell barrier, in endocytosis of circulating androgens resulting in AR-transactivation of genes associated with endothelial cell homeostasis and signaling, and in "non-genomic signaling" mediated through cell surface receptors for circulating androgens. Aim 2 will determine if androgen-deprivation induced killing of prostate endothelial cells results in transient, or irreversible, perturbation of the endothelial cells of the prostate microvasculature resulting in dysregulation of the tissue androgenic milieu (characterized using LC/MS/MS) and in creation/unmasking of unique, targetable "epitopes" or "vascular addresses" (characterized using phage peptide-display technology). Aim 3 will identify the effect of androgen deprivation on genes and gene pathways that are differentially expressed in prostate CSCs compared to adult stem cells (ASCs), identify the cell surface "epitope" fingerprint of prostate ASCs/CSCs, and determine if perturbation of the stem cell "niche" results in epigenetically-modulated dysregulation of the HNF-4n transcription network in prostate CSCs. The data and reagents generated in Aims 1-3 will support the studies of Aim 4 focused on development of novel approaches for utilizing androgen-deprivation to enable prostate-specific therapies by validating that: androgen deprivation exposes the ASC/CSC to targeted therapy; transcytosis of circulating androgens can be inhibited without perturbation of endothelial cell homeostasis; and endothelial cell initiated signaling to ASCs/CSCs can be reprogrammed to induce the stem cell to exit the "niche" and commit to differentiation.